Astrocytes arise from multipotent neural stem cells and retain their capacity for division throughout their life span. This property is likely to make them susceptible for transformation and to contribute to the fact that astrocyte-derived tumors are the most common brain tumors in adults. Low-grade astrocytomas acquire their blood supply by propagating along the existing normal blood vessels in a process termed vessel cooption (Holash et al., 1999; Kim et al., 2002). This leads to diffuse invasion of tumor cells over long distances in the brain without formation of real tumor masses. As grade III astrocytomas progress to grade IV astrocytomas they grow in size, and to cope with the increased need for nutrients and oxygen they undergo an angiogenic switch. These most malignant forms of astrocytomas, glioblastoma multiforme, become highly vascularised and tumors appear more local than the low-grade astrocytomas. Unlike angiogenic tumor vasculature, which has been one of the main focuses of cancer research during last years, the biology of the co-opted vascular beds is poorly understood.
The prognosis for patients suffering from brain tumors is poor and has not improved during the last decades. Especially low-grade astrocytomas are challenging because they have shown to be unreachable by conventional treatment strategies such as radiation or surgery. Furthermore, they would remain in the brain after anti-angiogenic therapies. The inhibition of tumor angiogenesis has proven to be an efficient therapeutic strategy to treat a variety of malignant tumors. However, systemic anti-angiogenic treatment of malignant brain tumors seemed to lead to an increased number of satellite tumors in experimental animal models and might even encourage tumor cells to a more invasive phenotype (Kunkel et al., 2001; Rubenstein et al., 2000). Therefore, new therapies are urgently needed to prolong the survival of patients suffering from these extremely aggressive tumors.
Recently it has become apparent that each tissue expresses its own specific set of cell surface proteins on vascular endothelial cells. In addition, many pathological conditions including tumors, diabetes, atherosclerosis and inflammatory diseases, add their disease-specific tags to the endothelium of the affected tissues. In vivo biopanning using phage displayed peptide libraries is a powerful tool to profile this vascular heterogeneity and map regional and disease-specific differences in the vasculature.
By using this technology, we have isolated several peptides homing specifically to the tumor vasculature (Laakkonen and Ruoslahti, 2006; Ruoslahti, 2002). We have also shown that the vasculature of a pre-malignant lesion differs from that of a full-blown tumor and from the vasculature of the corresponding normal organ (Hoffman et al., 2003; Joyce et al., 2003). Some of the tumor-homing peptides recognize common angiogenesis markers and are capable of homing to several types of tumors while other peptides recognize tumor-type specific differences. Recently, we have isolated peptides with novel homing specificities, for example peptides that home to tumor lymphatic vessels (Zhang et al. 2006; Laakkonen et al. 2004; Laakkonen et al. 2002).